Syntaxin 1B (STX1B) is a core component of the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that is critical for the exocytosis of synaptic vesicles in the presynapse. SNARE-mediated vesicle fusion is assisted by Munc18-1, which recruits STX1B in the auto-inhibited conformation, while Munc13 catalyses the fast and efficient pairing of helices during SNARE complex formation. Mutations within the STX1B gene are associated with epilepsy. Here we analysed three STX1B mutations by biochemical and electrophysiological means. These three paradigmatic mutations cause epilepsy syndromes of different severity, from benign fever-associated seizures in childhood to severe epileptic encephalopathies. An insertion/deletion (K45/RMCIE, L46M) mutation (STX1B^InDel), causing mild epilepsy and located in the early helical H_abc domain, leads to an unfolded protein unable to sustain neurotransmission. STX1B^G226R, causing epileptic encephalopathies, strongly compromises the interaction with Munc18-1 and reduces expression of both proteins, the size of the readily releasable pool of vesicles, and Ca²⁺-triggered neurotransmitter release when expressed in STX1-null neurons. The mutation STX1B^V216E, also causing epileptic encephalopathies, only slightly diminishes Munc18-1 and Munc13 interactions, but leads to enhanced fusogenicity and increased vesicular release probability, also in STX1-null neurons. Even though the synaptic output remained unchanged in excitatory hippocampal STX1B^+/− neurons exogenously expressing STX1B mutants, the manifestation of clear and distinct molecular disease mechanisms by these mutants suggest that certain forms of epilepsies can be conceptualized by assigning mutations to structurally sensitive regions of the STX1B−Munc18-1 interface, translating into distinct neurophysiological phenotypes.

中文翻译：

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引起癫痫的STX1B突变将改变的蛋白质功能转变为小鼠神经元中不同的表型。

Syntaxin 1B（STX1B）是N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合物的核心成分，对于突触前突触小泡的胞吐作用至关重要。SNARE介导的囊泡融合是由Munc18-1辅助的，Munc18-1以自动抑制的构象募集STX1B，而Munc13则在SNARE复合物形成过程中催化了快速有效的螺旋配对。STX1B基因内的突变与癫痫有关。在这里，我们通过生化和电生理手段分析了三个STX1B突变。这三种范例突变会导致不同严重程度的癫痫综合征，从儿童时期的良热相关性癫痫发作到严重的癫痫性脑病。插入/删除（K45 / RMCIE，L46M）突变（STX1B导致轻度癫痫并位于早期螺旋H _abc结构域的^InDel导致无法维持神经传递的未折叠蛋白。STX1B ^G226R会引起癫痫性脑病，强烈损害与Munc18-1的相互作用并降低两种蛋白质的表达，易于释放的囊泡大小以及在STX1无神经元中表达的Ca ²⁺触发的神经递质的释放。突变STX1B ^V216E也引起癫痫性脑病，仅略微减少了Munc18-1和Munc13的相互作用，但在STX1无效的神经元中也导致融合性增强和囊泡释放可能性增加。即使在兴奋性海马中突触输出保持不变STX1B ^+/-外源表达STX1B突变体的神经元，这些突变体清楚而独特的分子疾病机制的表现表明，可以通过将突变分配给STX1B-Munc18-1接口的结构敏感区来概念化某些形式的癫痫病神经生理学表型。